Safe and efficient drug delivery techniques have been studied for a long time, and various delivery systems and techniques have been developed, in the field of treatment using negatively charged drugs, particularly nucleic acid substances. Particularly, delivery techniques employing viral delivery systems based on an adenovirus or a retrovirus, and non-viral delivery systems based on cationic lipids or cationic polymers have been developed.
However, it is known that the techniques employing the viral delivery systems are exposed to risks, including non-specific immune responses, and that their commercial use presents a number of problems due to the production processes being complex. For this reason, a recent research trend is to overcome the shortcomings of viral delivery systems using non-viral delivery systems based on cationic lipids or cationic polymers. Such non-viral delivery systems are less efficient than viral delivery systems, but have the advantages of being accompanied by fewer side effects in vivo and having a low production cost.
Among non-viral delivery system formulations, polycationic polymers that electrostatically bind to nucleic acid substances to form nucleic acid-polymer complexes have been used, but there are a number of problems that occur when actually used because of the cytotoxicity of the polycationic charges.
Also, cationic lipids can be used, but are difficult to use in vivo, because the stability of nucleic acid-lipid complexes in blood is low. Moreover, it has been attempted to use ionic liposomes, including cationic lipids, neutral lipids and fusogenic lipids, as systemic delivery systems, but the cationic lipids are complex to synthesize and are still cytotoxic, and the efficiency of intracellular nucleic acid delivery thereof is low.
In addition, techniques in which complexes of cationic lipids with siRNA are formed and the complexes are entrapped in the micelles of amphiphilic block copolymers are known. However, the synthesis and purification process of the cationic cholesterol lipids that are used in these techniques are complex.
Meanwhile, many diseases are caused by an increased expression of disease-related genes which happens because of various factors or by abnormal activity which is caused by mutation. siRNA (small interfering RNA) inhibits the expression of a specific gene in a sequence-specific manner at the post-transcriptional stage, and receives a great deal of attention as a gene therapeutic agent. Particularly, due to its high activity and precise genetic selectivity, siRNA is expected as a nucleic acid therapeutic agent that can substitute for existing antisense nucleotides or ribozymes. siRNA is a short double-stranded RNA molecule composed of 15-30 nucleotides and cleaves the mRNA of a gene having a nucleotide sequence complementary thereto to inhibit the expression of the gene.
However, siRNA is rapidly degraded by nucleases in the blood and does not easily pass through the cell membrane because it is negatively charged. For this reason, in order to use siRNA as a therapeutic agent, it is required to use a composition which allows siRNA to be efficiently delivered into a targeted cell or an organ while siRNA circulates in the blood over a long period.